1. Field of the Invention
This invention relates to the application of paired and/or coupled pacing stimulation to effect post-extrasystolic potentiation (PESP) cardiac output augmentation with physiologic sensor feedback for reducing cardiac muscle fatigue and the risk of inducing life threatening arrhythmias.
2. Description of a Prior Art
Atrioventricular (AV) synchronous pacing systems, including DDD pacing systems marketed by Medtronic, Inc. and other companies, have been prescribed for treatment of a variety of bradycardia conditions in patients, including, in certain instances, patients suffering from congestive heart failure. Such patient groups tend to do much better hemodynamically with AV synchronous pacing due to the added contribution of atrial contraction to ventricular filling and subsequent contraction. However, fixed or physiologic sensor driven rate responsive pacing in such patients does not always lead to improvement in cardiac output and alleviation of the symptoms attendant to such disease processes. Several forms of heart failure are also associated with compromised diastolic function and/or decreased atrial and ventricular compliance. These may be conditions associated with chronic disease processes or complications from cardiac surgery with or without specific disease processes. Most heart failure patients do not normally suffer from a defect in the conduction system leading to ventricular bradycardia, but rather suffer from symptoms which may include a general weakening of the contractility of the cardiac muscle, attendant enlargement thereof, depressed ventricular filling characteristics, edema, and disruption in systemic blood pressure. All these disease processes lead to insufficient cardiac output to sustain even moderate levels of exercise and proper function of other body organs. Such patients are normally treated with drug therapies, including digitalis, which may lead to toxicity and loss of effectiveness.
In the early days of implantable cardiac pacing, it was observed that paired and triggered (also referred to as coupled) pacing with relative short interpulse intervals (150 to 250 milliseconds in dogs and about 300 milliseconds in human subjects) results in electrical depolarizations without attendant mechanical myocardial contractions. The result of the second pulse, applied within the relative refractory period of the first paced or spontaneous depolarization, is to prolong the refractory period and effect a slowing of the heart rate from its spontaneous rhythm. This slowing effect has been employed since that time in many applications, including the treatment of atrial and ventricular tachycardias, where a single pulse or a burst of pulses are coupled to a spontaneous tachycardia event with a coupling interval that is shorter than and can be set as a fraction of the tachycardia interval as taught, for example, in U.S. Pat. No. 3,857,399 to Dr. Fred Zacouto and U.S. Pat. No. 3,939,844 to Michael Pequiguot. The slowing of the heart rate by coupled pacing is accompanied by the ability to increase or decrease the rate with subsequent paired pacing within wide limits.
Paired and coupled stimulation also cause a potentiation of contractile force effect through a phenomenon known as post-extrasystolic potentiation. The effect can be performed continuously provided there is a continuous string of extrasystoles. When removed, the effect decays over the next few contractions until the base line levels of force production are reached. The extent of the potentiation is closely related to the prematurity of the extrasystole.
Early investigators conducted a large number of animal and human studies employing paired and coupled stimulation of the atrial and ventricular chambers in an effort to employ the PESP effect for the ventricles therapeutically. A history of the investigations and studies conducted in the 1960's is published in the book Cardiac Pacemakers by Harold Siddons and Edgar Sowton, M.D., 1968, pages 201-216 and the bibliography listing articles referenced therein. In addition, medical device manufacturers, including Medtronic, Inc., offered paired and coupled pacing pulse stimulators over many years to investigators conducting such studies. The Medtronic.RTM. Model 5837 R-wave coupled pulse generator is an example of such non-implanted pulse generators which were used by investigators to conduct paired and coupled pacing studies where both the pacing rate and the coupling intervals were manually adjustable.
In the studies conducted with such systems, and as reported in the above-referenced Siddons et al. book and papers referenced therein, it was also observed that PESP effect is more marked in animals and patients when myocardial function is poor rather than normal. It was also observed that the "electro-augmentation" of the force of contraction provided by the PESP effect is not increased by a third electrical stimulus. Thus, usually only a second pacing pulse, either paired with a preceding pacing pulse or as triggered by a preceding spontaneous cardiac event, was employed in further studies. Such studies have included the delivery of paired or triggered pacing pulses to either the ventricle or the atrium. It was observed that in those patients that have normal AV conduction, the ventricular rate could be slowed by paired or coupled stimulation of the atrium. However, the ventricular contraction was not found to be electro-augmented by such atrial stimulation.
Other physiologic effects of the paired and coupled pacing included in the PESP effects described above attendant changes in the contractile force of the myocardium are the peak systolic blood pressure, the rate of contraction of the ventricular muscle with a resulting increase of the rate of rise of intraventricular pressure (dP/dt), an increase in coronary blood flow, and an increase in the oxygen uptake of the heart per beat. Investigators observed that PESP was accompanied by an increase in the myocardial oxygen consumption of 35% to 70% as compared with single pulse stimulation at the same rate. The addition of a third stimulus increased the myocardial oxygen uptake even further without any attendant observed increase in cardiac contractile force. The alterations in coronary flow roughly parallel the oxygen consumption of the heart as observed in such studies.
The marked potentiation effect produced by paired stimulation led certain investigators to study the use of the technique in the treatment of acute heart failure induced in dogs. Improvements in left ventricular performance and cardiac output produced by such paired pacing in these dogs was observed by several investigators. In other studies conducted on relatively normal dogs' hearts, it was confirmed that paired pacing offered no increase in cardiac output, most likely due to reflex compensation.
The above described observations from the Siddons book also appear in part in the articles "The Hemodynamic Effect of Slowing the Heart Rate by Paired or Coupled Stimulation of the Atria," American Heart Journal, Vol. 73, No. 3, pp. 362-368, March, 1967, by John W. Lister, M.D., et al., and "Electro-augmentation of Ventricular Performance and Oxygen Consumption by Repetitive Application of Paired Electrical Stimuli," Circulation Research, Vol. 16, pp. 332-342, April, 1965, by John Ross, Jr., M.D., et al.
Investigations on human subjects in those years had been less promising, at least with respect to the potentiation treatment of patients in severe congestive heart failure. In certain reported cases, however, some improvement was observed. Many of these preliminary studies in humans were conducted usually in patients whose disease state and medication (or lack thereof) rendered their hearts overly susceptible to ventricular fibrillation. It was concluded at that time that, because the second pulse of each pair had to be applied at or close to the vulnerable period in the cardiac cycle (outside the absolute refractory period, but inside the relative refractory period), the risk of provocation of ventricular fibrillation was unacceptably high in a patient whose fibrillation threshold was low. Moreover, it was observed that the fibrillation threshold varied considerably under the influence of hypoxia, electrolyte disorders, drugs, and other factors.
In addition, sophisticated implantable pulse generators and sensors were unavailable at the time and the implantation usually entailed open chest surgery to affix epicardial electrodes, which was contra-indicated in severely ill congestive heart failure patients.
The period of takeover of the ventricular rhythm by the paired or coupled stimulation was believed to be especially risky inasmuch as the vulnerable period in the cardiac cycle varied with the prematurity of an extrasystolic beat or the underlying cardiac rate. Since the length of the refractory interval was initially unknown, investigators working with a patient had to detect the end of the absolute refractory interval by trial and error, and oft times delivered the paired or coupled pulse into the vulnerable period. In addition, most physicians found these procedures and long-term patient care to be excessively time-consuming.
It should be noted that with the pacing technology at that time, the pacing threshold was close to the fibrillation threshold. In any case, the difficulty and perceived degree of risk with fairly primitive technology discouraged physicians from further considering paired and coupled pacing to augment ventricular cardiac function in congestive heart failure patients.
The most striking improvements were observed in reducing the heart rate in patients suffering from runs of either atrial or ventricular tachycardia which could not be controlled by drugs. Subsequent developments in manually initiated or automatic triggering of fixed rate or rate adaptive overdrive burst and scanning pacing have been incorporated in antitachycardia control devices including multi-programmable, multi-function cardiac pacemakers and pacemaker-cardioverter-defibrillator devices. However, little further work appears to have been conducted in regard to the use of paired and coupled stimulation to induce the PESP effects in the treatment of patients suffering from cardiac disease processes not amenable to treatment by conventional pacing or higher energy stimulation. In addition, the use of atrial paired or coupled pacing in the attempt to "potentiate" atrial cardiac contractions to produce atrial PESP effects remain incomplete.